New approach methodologies: A quantitative in vitro to in vivo extrapolation case study with PFASs

and polyfluoroalkyl substances (PFASs) have been associated with increased blood lipids in humans. Perfluorooctanoic acid (PFOA) has been also linked with elevated alanine transferase (ALT) serum levels in humans, and in rodents the liver is a main target organ for many PFASs. With the focus on New...

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Bibliographic Details
Published in:Food and chemical toxicology 2023-02, Vol.172, p.113559, Article 113559
Main Authors: Fragki, Styliani, Louisse, Jochem, Bokkers, Bas, Luijten, Mirjam, Peijnenburg, Ad, Rijkers, Deborah, Piersma, Aldert H., Zeilmaker, Marco J.
Format: Article
Language:English
Subjects:
Alkanesulfonic Acids
Caprylates - toxicity
Environmental Pollutants
Fluorocarbons - toxicity
HBM4EU
HepaRG cells
Humans
Lipids
Oral equivalent effect dose
PBK modelling
PFASs
QIVIVE
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Summary:and polyfluoroalkyl substances (PFASs) have been associated with increased blood lipids in humans. Perfluorooctanoic acid (PFOA) has been also linked with elevated alanine transferase (ALT) serum levels in humans, and in rodents the liver is a main target organ for many PFASs. With the focus on New Approach Methodologies, the chronic oral equivalent effect doses were calculated for PFOA, PFNA (perfluorononanoic acid), PFHxS (perfluorohexanesulfonic acid) and PFOS (perfluorooctane sulfonic acid) based on in vitro effects measured in the HepaRG cell line. Selected in vitro readouts were considered biomarkers for lipid disturbances and hepatotoxicity. Concentration-response data obtained from HepaRG cells on triglyceride (TG) accumulation and expression changes of 12 selected genes (some involved in cholesterol homeostasis) were converted into corresponding human dose-response data, using physiologically based kinetic (PBK) model-facilitated reverse dosimetry. Next to this, the biokinetics of the chemicals were studied in the cell system. The current European dietary PFASs exposure overlaps with the calculated oral equivalent effect doses, indicating that the latter may lead to interference with hepatic gene expression and lipid metabolism. These findings illustrate an in vitro-in silico methodology, which can be applied for more PFASs, to select those that should be prioritized for further hazard characterization.
ISSN:0278-6915
1873-6351
1873-6351
DOI:10.1016/j.fct.2022.113559